Several routes to N—H or N-alkyl 2-propynamides are known, but they all suffer from severe drawbacks from a commercial manufacturing point of view. They also do not allow for the control of the quality of the product in a way that is requested for the production of pharmaceutical intermediates. Therefore it is a demand for efficient methods to manufacture N—H or N-alkyl 2-propynamide circumventing these problems.
As very versatile intermediates, different synthetic methods to manufacture derivatives of 2-propynamide have been described in current literature.
J. Org. Chem. 30, 2660 [1965] and J. Org. Chem. 63, 5050 [1998] report the synthesis of propynamides, including propynamide, N-methylpropynamide and N-ethylpropynamide, by the reaction of methyl propiolate with the appropriate amine, at very low temperatures (such as between −30° C. and −60° C., even up to −78° C.) mainly in aqueous methanol. Disadvantageous to this approach is the necessity to carry out this reaction at low temperature between −30° C. and −60° C. to favor the formation of amide product over Michael adduct. Low temperatures are a distinct problem on larger production scale, since they require high investments in cooling equipment and enormous energy consumption to maintain the low temperature, therefore this process is inadequate for commercial manufacture. Further, such very low temperatures may make it difficult to use water as a solvent.
Another amide bond formation strategy involves the use of activated propiolic acid derivatives preformed and/or formed in situ. Examples are propiolic anhydride (J. Chem. Soc. Perkin I 1493 [1975]), propiolyl chloride (J. Org. Chem. 39, 725 [1974] and J. Org. Chem. 63, 9069 [1998]) or mixed anhydride (Synthetic Communications 23, 2003 [1993]). In these approaches the above-mentioned low temperature condition can be avoided. The disadvantage of these methods is however the fact that additional chemical steps have to be performed to generate these activated intermediates and non-aqueous solvents have to be used, since these intermediates are unstable in water. Therefore these methods are from an ecological point of view unfavorable, since a tremendous amount of waste is generated in the case of a commercial application.
An enzymatic approach is described in Tetrahedron 49, 4007 [1993] with a lipase catalyzed reaction between ethyl propiolate and anillines to afford the corresponding amide at 25° C.˜60° C. However this reaction has not been shown for the title compounds of this invention and requires the use of special technology as well as highly toxic solvent carbon tetrachloride.
Therefore there is a strong need for a novel process to manufacture N—H or N-alkyl 2-propynamides, which renders the desired product in high quality and good chemical yield, and in an efficient and environmentally friendly manner.